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The "Quality of Life-Assessment of Growth Hormone Deficiency in Adults" Questionnaire: Can It Be Used to Assess Quality of Life in Hypopituitarism?¹

Departments of Internal Medicine and Surgery, University of Michigan and Veterans Administration Medical Centers, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Ariel Barkan, M.D., 3920 Taubman Center, Box 0354, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0354. E-mail: abarkan{at}umich.edu

	Abstract

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Patients with hypopituitarism often have a multitude of physical and psychological complaints, collectively referred to as low quality of life (QoL). It has been asserted that GH deficiency (GHD) is the causative factor, and improved QoL scores have been reported during GH replacement. Qol-assessment of GHD (QoL-AGHDA) is the newest psychometric instrument with the purportedly high specificity for the issues encountered by patients with GHD. QoL-AGHDA was administered to 30 normal control subjects, 20 patients with severe GHD, and 22 patients with active acromegaly. QoL-AGHDA scores in controls (3.3 ± 0.7) were significantly (P < 0.001) different from those in patients with hypopituitarism with unsubstituted GHD (10.6 ± 1.5) and active acromegaly (11.6 ± 1.6). However, QoL-AGHDA was unable to discriminate between the latter two groups, one with GHD and the other with GH excess. We conclude that as QoL-AGHDA cannot distinguish between the extremes of GH output, its ability to detect an improvement in QoL during GH replacement has to be viewed with skepticism. This can be dispelled only by double blind, placebo-controlled studies.

	Introduction

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THE GENERAL TERM quality of life (QoL) encompasses patients’ perceptions of physical and mental health, psychological reactions (anxiety, depression, etc.), subjective feelings of energy and vitality, as well as cognitive function and memory. Many studies have reported a decreased QoL in patients with adult GH deficiency (GHD) and QoL improvement after GH replacement (1, 2). However, most of these results were obtained in studies that were performed in an open design; thus, the placebo effect could not be excluded. In contrast, in studies performed in a single or double blind design and using a placebo control, no or little effect of GH replacement were noticed (3, 4). In a double blind, placebo-controlled, cross-over study (5), no difference between the GH and placebo arms was detected using Psychological General Well-Being Index or the Nottingham Health Profile. Although some positive effects of GH were noted in certain subclasses of the Hopkins Symptoms Check List, even that instrument failed to detect an overall superiority of GH over placebo. In another study of similar design (6), no improvement in the overall Nottingham Health Profile score was noticed after a double blind phase, but a significant improvement was noted after an additional 12 months of open label therapy. Similarly, after 6 months of supposedly double blind therapy, no difference was detected using a Symptom Check List-90 questionnaire, although a mild effect of GH was suggested by the Comprehensive Psychological Rating Scale (7). Importantly, in these studies, obvious GH side-effects occurred in 24–37% (6) to 70% (7) of patients, probably negating the effects of blinding (7). It has been suggested that the failure to detect a salutary effect of GH on QoL was due not to GH’s inherent lack of efficacy but, rather, to the lack of specificity and sensitivity of the questionnaires (8, 9). In an attempt to correct this problem, a new questionnaire, QoL-AGHDA (QoL-assessment of GHD in adults) has been developed (8). To this end, 35 young patients with GHD were repeatedly interviewed, and their areas of concern were identified. The final questionnaire, comprising 25 "yes/no" questions, was proposed to be relevant to the issues brought about by GHD: lack of assertiveness, concentration, memory, and energy; increased anxiety and depression; and difficulties in social interactions. The purported specificity of this questionnaire for GHD (10, 11) explains its use in many current studies assessing QoL in patients with hypopituitarism.

As the performance of QoL-AGHDA during GH therapy had never before been tested in a double blind, placebo-controlled design, the contribution of placebo effects to a declining (improving) AGHDA score is uncertain. Thus, it is interesting to assess the performance of AGHDA in populations with widely different GH status. If AGHDA scores are different in this setting, the ability of this questionnaire to correctly identify changes in QoL during GH administration to hypopituitary adults would be supported. If the reverse is true, AGHDA should be further validated in double blind, placebo-controlled trials. To this end, we studied QoL-AGHDA scores in patients with severe hypopituitarism and in those with active acromegaly.

	Materials and Methods

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The QoL-AGHDA questionnaire was administered during a routine clinical visit to 20 patients with severe adult-onset hypopituitarism and to 22 patients with clinically and biochemically active acromegaly. The purpose of the questionnaire was explained in detail to each patient, and oral informed consent was obtained. Plasma insulin-like growth factor I (IGF-I) levels were measured in blood samples taken at the same time using a commercially available chemiluminometric kit (Nichols Institute Diagnostics, San Juan Capistrano, CA). QoL-AGHDA questionnaires completed anonymously by the staff and faculty of the Divisions of Endocrinology and Neurosurgery in our institution were used as the control group. Plasma IGF-I was not measured in this group.

Hypopituitarism

The group consisted of 9 women and 11 men, with a mean age of 49.4 ± 2.3 yr. Severe hypopituitarism in all 20 subjects was defined as a combination of a history of pathological process in the hypothalamic-pituitary area, the need for at least 3 replacement therapies (glucocorticoid, T₄, and gonadal steroid), and plasma IGF-I that was low for the sex/age-adjusted normal range. Seven patients also required DDAVP to control their diabetes insipidus. The known duration of hypopituitarism was at least 4 yr. Five patients had nonfunctioning pituitary tumors, 1 had a macroprolactinoma, 3 had Rathke’s cleft cyst, 4 had craniopharyngioma, 2 had Sheehan’s syndrome, and 1 patient each had tuberculous meningitis, meningioma, pituitary abscess, hypophysitis, and postpubertal panhypopituitarism of unknown etiology. Surgery was performed in 14 cases, and 6 of those patients also had XRT. The patient with macroprolactinoma was treated with dopamine agonists, and the remaining 19 patients received only replacement hormonal therapy.

Acromegaly

A total of 22 patients with acromegaly completed the questionnaire. The diagnosis of active disease was established clinically and confirmed by abnormally elevated plasma IGF-I levels in all of them. There were 7 women and 15 men with a mean age of 46.7 ± 3.3 yr. The duration of active acromegaly was estimated to be between 4–45 yr. Ten patients were newly diagnosed, and 12 were previously treated with transsphenoidal surgery. Five of them also had XRT, and 5 were taking dopamine agonists and/or somatostatin analogs. Five patients were taking standard replacement hormonal therapy in various combinations, and the remaining 17 were deemed not to have pituitary hormonal deficits.

Statistical analysis was performed using two-tailed Student’s t tests; P < 0.05 was considered significant. Data are presented as the mean ± SE.

	Results

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In patients with hypopituitarism, mean plasma IGF-I was 44 ± 7 µg/L (normal, >90). In patients with acromegaly, mean plasma IGF-I was 662 ± 59 µg/L (normal, <318), significantly higher than in the hypopituitary group (P < 0.001).

The QoL-AGHDA score in normal controls was 3.3 ± 0.7 (range, 0–13), similar to the previously published data from other groups (8). This was significantly lower than in patients with hypopituitarism (10.6 ± 1.5; range, 0–23; P < 0.001) or in patients with active acromegaly (11.6 ± 1.6; range, 1–23; P < 0.001). There was no difference in QoL-AGHDA scores between patients with hypopituitarism and those with acromegaly (P > 0.5).

Due to a narrow range of plasma IGF-I levels in hypopituitary patients, the formal correlation analysis of AGHDA/IGF-I could not be performed with confidence. However, mean plasma IGF-I levels in the 12 patients with AGHDA scores equal to or below 13 (the highest value found in normal controls) and those in the 8 patients with AGHDA scores above 13 were similar (51.3 ± 9.8 vs. 41 ± 11.1 µg/L; P = 0.5). In patients with acromegaly, regression analysis between AGHDA scores and plasma IGF-I showed no correlation (r² = 0.058). Newly diagnosed patients had higher plasma IGF-I (P < 0.05) than previously treated patients (828 ± 92 vs. 524 ± 52 µg/L), but their AGHDA scores were similar (10.8 ± 2.2 vs. 12.3 ± 2.3; P = 0.5).

	Discussion

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These data show that the QoL-AGHDA questionnaire, designed specifically to assess physical and mental discomfort brought about by GHD, fails to distinguish between the state of severe GHD and the state of GH excess.

Currently, improvement in the QoL emerges as a leading indication for GH therapy in hypopituitary adults. However, several unresolved questions cast doubt on the justification for this practice. First, several well controlled studies could not find evidence to support the existence of low QoL in that group (12, 13, 14). Second, QoL is an inherently subjective parameter and, as such, is very susceptible to the placebo effect. Importantly, no change in QoL was observed in several studies of GH replacement that employed a single blind, placebo-controlled design (3, 4). However, remarkable improvement in QoL was seen in the same patients once an open label administration of GH was commenced (3, 4). In one double blind placebo-controlled study of an 18-month duration, there was no change in QoL in GH-treated patients as measured by a multitude of sophisticated psychometric tests (14). In several other studies employing a double blind placebo-controlled design (5, 6, 7), GH was not superior to placebo, as demonstrated by the overall results of several psychometric instruments. Whether positive effects of GH in some of the multiple subdivisions of a particular instrument (5, 7) were due to the use of multiple t tests is uncertain. Obviously, a high incidence of GH-related side-effects, between 24–70% (6, 7) probably unblinded the treatment arm, as stated by the researchers (6). One potential explanation for these findings would be that neither GHD nor GH sufficiency plays any role in determining the QoL. This is indirectly supported by a lack of correlation between QoL-AGHDA scores and the main biological mediator of GH activity, IGF-I, as seen by Murray et al. (9) and also in the patients presented here.

An alternative explanation would be that the QoL tests employed in the studies failing to document an effect of GH therapy were not specific for hypopituitarism. It has been asserted that GHD in hypopituitary adults affected QoL in a peculiar manner, and that only a psychometric instrument specifically designed for and validated in that group would be sensitive and specific enough to be reliably used in the research studies and in clinical practice (2, 8). That was the impetus behind the development of the QoL-AGHDA questionnaire. Using this instrument, low QoL in hypopituitary adults at diagnosis and its improvement after GH therapy have been demonstrated (9). The individuals with the lowest QoL (highest AGHDA scores) had the most improvement after GH treatment (9). The data presented here support the idea of higher QoL-AGHDA scores in adult hypopituitary subjects. This is not surprising, because any chronic illness requiring invasive treatments and life-long follow-up and associated with impaired bodily functions would probably worsen the QoL by any definition. Thus, the use of healthy individuals as a control group may not be entirely appropriate. Unfortunately, the performance of QoL-AGHDA was never assessed in patients with non-GH-related chronic illness. This is the likely reason why similarly high AGHDA scores were seen in this study in patients with severe GHD as well as in those with uncontrolled acromegaly and GH hypersecretion. Thus, it becomes conceptually difficult to attribute high AGHDA scores in patients with severe hypopituitarism and low IGF-I to GHD. Moreover, an improvement in AGHDA scores with GH treatment becomes biologically inexplicable. Importantly, the performance of QoL-AGHDA questionnaires in GH-treated hypopituitary adults had never been assessed in a double blind, placebo-controlled design. Thus, the existing reports of the salutary effects of GH in hypopituitarism that are based on QoL-AGHDA need to be viewed with reservation. Studies validating QoL-AGHDA for that purpose should be performed in a double blind, placebo-controlled fashion.

	Footnotes

 
¹ This work was supported by the Department of Veterans Affairs Medical Research Service and NIH Grant DK-38449.

Received September 19, 2000.

Revised November 20, 2000.

Revised December 28, 2000.

Accepted January 16, 2001.

	References

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